Cyclic carbamate analogues of pilocarpine

A number of pilocarpine analogues containing the (S)-3-ethyl-4-[(4'-imidazolyl)methyl]-2-oxazolidinone (9) structural feature were synthesized from L-histidine. With 1-benzyl-L-histidine as the key intermediate, a regiospecific synthetic route was developed to the N pi-methyl derivative 8. The regiochemistry of the alkylation of the imidazole nucleus was determined by measuring proton cross-ring coupling constants in the high-field 1H NMR. The effects on muscarinic receptors of these variously alkylated derivatives 6-10 were studied on isolated guinea pig ileum. The derivatives in which the imidazole nitrogen was unsubstituted (9), N tau-methylated (10), and N pi-methylated (8) were cholinergic muscarinic agonists with an increasing order of potency; compounds 6 and 7 were inactive. Analogue 8 with the same substitution pattern as pilocarpine was equipotent with pilocarpine, making these hydrolytically stable carbamate derivatives potentially useful drugs.